RAGE and ICAM-1 cooperate in mediating leukocyte recruitment during acute inflammation in vivo

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 841-849 ◽  
Author(s):  
David Frommhold ◽  
Anna Kamphues ◽  
Ingrid Hepper ◽  
Monika Pruenster ◽  
Ivan K. Lukić ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Leukocyte Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Adhesion Assay ◽  
In Vivo Experiments ◽  
Relative Contribution ◽  
Soluble Rage ◽  
Glycation End Products

The receptor for advanced glycation end products (RAGE) contributes to the inflammatory response in many acute and chronic diseases. In this context, RAGE has been identified as a ligand for the β2-integrin Mac-1 under static in vitro conditions. Because intercellular adhesion molecule (ICAM)-1 also binds β2-integrins, we studied RAGE−/−, Icam1−/−, and RAGE−/−Icam1−/− mice to define the relative contribution of each ligand for leukocyte adhesion in vivo. We show that trauma-induced leukocyte adhesion in cremaster muscle venules is strongly dependent on RAGE and ICAM-1 acting together in an overlapping fashion. Additional in vivo experiments in chimeric mice lacking endothelium-expressed RAGE and ICAM-1 located the adhesion defect to the endothelial compartment. Using microflow chambers coated with P-selectin, CXCL1, and soluble RAGE (sRAGE) demonstrated that sRAGE supports leukocyte adhesion under flow conditions in a Mac-1– but not LFA-1–dependent fashion. A static adhesion assay revealed that wild-type and RAGE−/− neutrophil adhesion and spreading were similar on immobilized sRAGE or fibrinogen. These observations indicate a crucial role of endothelium-expressed RAGE as Mac-1 ligand and uncover RAGE and ICAM-1 as a new set of functionally linked adhesion molecules, which closely cooperate in mediating leukocyte adhesion during the acute trauma-induced inflammatory response in vivo.

scholarly journals Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1484-1490 ◽  
Author(s):  
BH Kushner ◽  
NK Cheung
Keyword(s):  
Monoclonal Antibody ◽  
Adhesion Molecules ◽  
Leukocyte Adhesion ◽  
Neuroblastoma Cell ◽  
Intercellular Adhesion Molecule ◽  
Target Cells ◽  
Intercellular Adhesion Molecule 1 ◽  
Gm Csf

We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM- CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.

PPARγ Regulates the Anti-Inflammatory Effects of Carbon Monoxide on Macrophages: A Gene Profiling Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3445-3445
Author(s):  
Martin Bilban ◽  
Sherrie L. Otterbein ◽  
Emeka Ifedigbo ◽  
Keiji Enjyoji ◽  
Anny Usheva ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Inflammatory Response ◽  
Acute Phase Proteins ◽  
Expression Patterns ◽  
Endotoxic Shock ◽  
Gene Profiling ◽  
In Vivo Experiments ◽  
Anti Inflammatory

Abstract Carbon monoxide (CO) at low concentrations has generated recent interest due to its ability to modulate the inflammatory response associated with chronic graft rejection, vascular injury and septic shock. Both in vivo and in vitro CO can inhibit the expression of pro-inflammatory genes such as TNFα in macrophages while simultaneously increasing the expression of the anti-inflammatory cytokine IL-10. The mechanisms by which this occurs are still unclear. To better understand the mechanisms underlying the effects of CO, we employed the Affymetrix GeneChip technology to evaluate the time-dependent expression patterns of >12,000 genes in macrophages stimulated with bacterial endotoxin (LPS) in the presence or absence of a low concentration of CO previously demonstrated to evoke an anti-inflammatory response. We were particularly interested whether CO would, by itself, modulate in a specific manner the expression of proteins that might explain the anti-inflammatory effects observed following subsequent administration of endotoxin. RAW 264.7 murine macrophages were grown to 75% confluency and then exposed to CO (250 ppm) for 3 hr prior to administration of LPS (10 ng/ml). At 0, 15, 30, 60, 120 and 240 min thereafter, total RNA was isolated by standard methods and the RNA was then labeled and hybridized to U74Av2 GeneChips. Of >12,000 genes assessed, 116 of 270 that were LPS-responsive were affected by CO treatment. CO inhibited the majority of LPS-induced pro-inflammatory cytokines and acute phase proteins including expression of early growth response-1 (Egr-1), a transcription factor that serves as a central intermediary regulating many genes. Egr-1 was nearly completely inhibited by CO as was Egr-1-dependent expression of tissue factor (TF) and PAI-1. Treatment of cells with CO alone led to a rapid early increase in PPARγ, the expression of which was essential for the anti-inflammatory effects of CO. Inhibition of PPARγ using the selective chemical inhibitor GW9662 reversed the CO inhibitory effects on LPS-induced Egr-1 and TF expression. Correlative in vivo experiments in mice showed that CO pre-treatment blocked endotoxin-induced Egr-1 expression and decreased markers of lung inflammmation the effects of which were also lost with inhibition of PPARγ. Our analyses of gene expression patterns has led to the first molecular understanding of how treatment with CO, in this case by inducing PPARγ, blocks the pro-inflammatory response. These experiments provide novel insights into the mechanisms and pathophysiology of endotoxic shock and identify cellular targets by which CO mediates these cytoprotective effects.

BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 5040-5049 ◽  
Author(s):  
Thomas Helbing ◽  
René Rothweiler ◽  
Elena Ketterer ◽  
Lena Goetz ◽  
Jennifer Heinke ◽  
...  
Keyword(s):  
Vascular Endothelial Cells ◽  
Ex Vivo ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Bmp Signaling ◽  
In Vivo Models ◽  
In Vivo Experiments ◽  
And Migration

Abstract The endothelium plays a pivotal role in vascular inflammation. Here we study bone morphogenetic protein (BMP) signaling in endothelial inflammation and in particular the role of BMPER, an extracellular BMP modulator that is important in vascular development and angiogenesis. Using the BMP antagonist dorsomorphin or BMP2 as an agonist we show that BMP signaling is essential for the inflammatory response of vascular endothelial cells as demonstrated by intravital microscopy. We found that BMPER is decreased in inflammation similar to vascular protective genes like KLF2 and eNOS. Using in vitro and in vivo models we show that BMPER is down-regulated through the TNFα-NFκB-KLF2 signaling pathway. Functionally, lack of BMPER induced by siRNA or in BMPER+/− mice confers a proinflammatory endothelial phenotype with reduced eNOS levels and enhanced expression of adhesion molecules leading to increased leukocyte adhesion and extravasation in ex vivo and in vivo experiments. Vice versa, addition of BMPER exerts endothelium protective functions and antagonizes TNFα induced inflammation. Mechanistically, we demonstrate that these effects of BMPER are dependent on BMP signaling because of enhanced NFκB activity. In conclusion, the BMP modulator BMPER is a new protective regulator of vascular inflammation that modulates leukocyte adhesion and migration in vitro and in vivo.

scholarly journals PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction

1999 ◽  
Vol 277 (3) ◽  
pp. H1007-H1013 ◽  
Author(s):  
Ronald J. Korthuis ◽  
Dean C. Gute ◽  
Frank Blecha ◽  
Chris R. Ross
Keyword(s):  
Time Course ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Intercellular Adhesion Molecule ◽  
Neutrophil Adhesion ◽  
Intercellular Adhesion Molecule 1 ◽  
Protein Leakage ◽  
Oxidant Production

We and others have previously demonstrated that intestinal ischemia-reperfusion (I/R) is associated with a large increase in oxidant production that contributes to microvascular barrier disruption in the small bowel. It has been suggested that the bulk of tissue damage during reperfusion can be attributed to adherent, activated neutrophils. From these observations, we hypothesized that pretreatment with PR-39, an endogenous neutrophil antibacterial peptide that is also a potent inhibitor of the neutrophil NADPH oxidase, would prevent postischemic oxidant production and the development of oxidant-dependent sequelae to I/R such as increased venular protein leakage. To test this postulate, oxidant production, venular protein leakage, leukocyte adhesion, and leukocyte emigration were monitored during reperfusion in control (no ischemia) rat mesenteric venules and in mesenteric venules subjected to I/R alone or PR-39 + I/R. Treatment with a single intravenous bolus injection of PR-39 (administered at a dose to achieve an initial blood concentration of 5 μM) abolished I/R-induced leukocyte adhesion and emigration in vivo. In vitro studies indicated that PR-39 prevents platelet-activating factor-induced neutrophil chemotaxis as well as phorbol myristate acetate (PMA)-stimulated intercellular adhesion molecule-1 expression by cultured endothelial cells. PR-39 pretreatment of rat neutrophils also blocked PMA-stimulated neutrophil adhesion to activated endothelial monolayers. In vivo, I/R was associated with a marked and progressive increase in oxidant production and venular protein leakage during reperfusion, effects that were abolished by PR-39 treatment. The results of this study indicate that PR-39 completely abolishes postischemic leukocyte adhesion and emigration. The time course for inhibition of oxidant production by PR-39 suggests that its antiadhesive properties account for this effect of the peptide. PR-39 may thus be therapeutically useful for prevention of neutrophil adhesion and activation during the postischemic inflammatory response.

scholarly journals Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1484-1490 ◽  
Author(s):  
BH Kushner ◽  
NK Cheung
Keyword(s):  
Monoclonal Antibody ◽  
Adhesion Molecules ◽  
Leukocyte Adhesion ◽  
Neuroblastoma Cell ◽  
Intercellular Adhesion Molecule ◽  
Target Cells ◽  
Intercellular Adhesion Molecule 1 ◽  
Gm Csf

Abstract We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM- CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.

scholarly journals Minocycline Impedes African Trypanosome Invasion of the Brain in a Murine Model

2006 ◽  
Vol 50 (5) ◽  
pp. 1798-1804 ◽  
Author(s):  
Willias Masocha ◽  
Martin E. Rottenberg ◽  
Krister Kristensson
Keyword(s):  
Adhesion Molecule ◽  
Leukocyte Adhesion ◽  
Brain Parenchyma ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Necrosis Factor Alpha ◽  
Loss Of Weight ◽  
The Brain

ABSTRACT Passage of Trypanosoma brucei across the blood-brain barrier (BBB) is a hallmark of late-stage human African trypanosomiasis. In the present study we found that daily administration of minocycline, a tetracycline antibiotic, impedes the penetration of leukocytes and trypanosomes into the brain parenchyma of T. brucei brucei-infected C57BL/6 mice. The trypanosome-induced astrocytic and microglial reactions were reduced in the minocycline-treated mice, as were the levels in the brain of transcripts encoding adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and endothelial-leukocyte adhesion molecule 1 (E-selectin); the inflammatory cytokines tumor necrosis factor alpha, interleukin-1α (IL-1α), IL-1β, IL-6, and gamma interferon; and matrix metalloprotease 3 (MMP-3), MMP-8, and MMP-12. Loss of weight occurring during infection with T. b. brucei was not observed after treatment of the mice with minocycline; these mice also survived longer than nontreated mice. Invasion of trypanosomes and leukocytes into the brain parenchyma most likely triggered the loss of weight and death of infected animals, since minocycline did not affect the growth of T. b. brucei either in vitro or in vivo or the levels of the transcripts encoding the cytokines and MMPs in the spleen. In conclusion, our data show that T. b. brucei invasion of the brain is related to that of leukocytes and that minocycline can ameliorate the disease in trypanosome-infected mice.

Inhibitory effects of epimedium herb water extract on the inflammatory response in vitro and in vivo

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
YC Oh ◽  
YH Jeong ◽  
WK Cho ◽  
SJ Lee ◽  
JY Ma
Keyword(s):  
Inflammatory Response ◽  
Water Extract ◽  
Inhibitory Effects

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

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